Muscle infarction in a young woman with brittle type 1 diabetes

We present the first case of muscle infarction in a 30-year-old woman who had a 5-year history of type 1 diabetes mellitus that was not complicated by nephropathy, retinopathy or neuropathy. All common causes of muscle infarction were excluded, particularly microangiopathy and a hypercoagulable state. The differential diagnosis included infection (pyomyositis, necrotic fasciitis), focal inflammatory myositis, vascular events, trauma, tumor and diabetic amyotrophy, all of which were excluded. In spite of good glycaemic control, her diabetes remained brittle; alternating states of transient acute hypoglycaemia and hyperglycaemia may have been responsible for the infarction. Brittleness resumed after treatment with subcutaneous insulin infusion using a portable pump. No recurrence of muscle infarction was observed during a 18-month follow-up.     

Comparison of hypertension, dyslipidaemia and hyperglycaemia between buckwheat seed-consuming and non-consuming Mongolian-Chinese populations in Inner Mongolia, China

1. In the present study, a total of 3542 Mongolians in two adjacent counties of Inner Mongolia, China, were randomly sampled in a cross-sectional study to assess the association of hypertension, dyslipidaemia and hyperglycaemia with lifetime consumption of buckwheat seed as a staple food. A sample group of 961 participants was also examined for fasting serum concentrations of lipids and glucose. 2. Frequent alcohol consumption significantly contributed to the high prevalence rate of hypertension in the pastureland Mongolian population. 3. The age-adjusted prevalence rate of hypertension in Kulun participants who consumed buckwheat seed as a staple food was 18.22% (95% confidence interval (CI): 16.95%, 19.49%), whereas that in Kezhuohou participants, who consumed corn as a staple food, was 23.31% (95% CI: 21.92%, 24.70%). A statistically significant difference was found between the two groups (P < 0.01). 4. Age-adjusted prevalence rates in Kulun participants compared with Kezhuohou participants for hypercholesterolaemia, hypertriglyceridaemia and abnormalities in low-density lipoprotein-cholesterol were 4.02% (95% CI: 2.24%, 5.80%) versus 7.76% (95% CI: 5.39%, 10.13%; P < 0.01), 26.58% (95% CI: 22.59%, 30.57%) versus 31.04% (95% CI: 26.59%, 35.13%; P < 0.05) and 4.66% (95% CI: 2.75%, 6.57%) versus 8.81% (95% CI: 6.30%, 11.32%; P < 0.01), respectively. 5. The age-adjusted prevalence rate of hyperglycaemia in Kulun participants was 1.56% (95% CI: 0.78%, 2.34%), whereas that in Kezhuohou participants was 7.70% (95% CI: 6.01%, 9.39%). The difference was significant (P < 0.01). 6. These findings suggest that the consumption of buckwheat seed may be a preventative factor for hypertension, dyslipidaemia and hyperglycaemia in the pastureland Mongolian population.     

Nodular glomerulosclerosis in patients without any manifestation of diabetes mellitus

AIM/METHODS: Diabetic nodular glomerulosclerosis is considered to be the specific renal lesion of diabetes mellitus (DM). However, some cases, in which nodular glomerulosclerosis was found without any manifestation of DM, have also occasionally been reported. We clinicopathologically examined seven cases without a prior history of DM. They consisted of six men and one woman with a mean age of 57 years, and included three cases with family history of DM and six cases with hypertension. RESULTS: Mean body mass index was 26.2 +/- 5.9 (means +/- SD) kg/m(2) and haemoglobin A1c 5.3 +/- 1.1% or haemoglobin A1 7.0 +/- 0.6%. Mean plasma glucose levels were 5.3 +/- 0.7 mmol/L at fasting and 10.1 +/- 1.9 mmol/L at 2 h of 75 g OGTT (normal: 1 patient; impaired glucose tolerance: 4 patients; DM: 2 patients). None of them showed diabetic retinopathy in fundoscopic ophthalmoscopy. Mean serum creatinine was 268 +/- 215 micromol/L, urinary protein 5.2 +/- 4.0 g/day, and three patients had mild haematuria. Renal biopsy revealed typical nodular glomerulosclerosis, a negative deposition based on an immunofluorescence study, and neither any significant electron dense deposits nor fibrils on electron microscopy. CONCLUSION: These patients at presentation had no overt clinical manifestations of glucose intolerance. Diabetic nodular glomerulosclerosis can occur in patients without overt DM, suggesting the role of factors additional to prolonged hyperglycaemia in the pathogenesis of this disorder.     

Pancreatic B-cell function is altered by oxidative stress induced by acute hyperglycaemia.

AIMS: Type 2 diabetes is preceded by a symptom-free period of impaired glucose tolerance (IGT). Pancreatic B-cell function decreases as glucose intolerance develops. In many patients with IGT, fasting blood glucose is within normal limits and hyperglycaemia occurs only postprandially. We examined whether pancreatic B-cell function changes during acute hyperglycaemia induced by oral glucose loading. METHODS: We calculated the insulinogenic index (I.I.) as an indicator of pancreatic B-cell function and measured serum levels of thioredoxin, a marker of cellular redox state, and 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative stress, during a 75-g oral glucose tolerance test (OGTT) in 45 subjects [24 patients with normal glucose tolerance (NGT), 14 with IGT and seven with Type 2 diabetes]. RESULTS: Thioredoxin levels decreased after glucose loading [66.1 +/- 23.7, *59.3 +/- 22.4, *49.3 +/- 21.2 and *37.7 +/- 18.0 ng/ml, fasting (0 min) and at 30, 60 and 120 min, respectively; *P < 0.001 vs. fasting]. In contrast, concentrations of 8-OHdG peaked at 30 min and then gradually decreased (0.402 +/- 0.123, *0.440 +/- 0.120, 0.362 +/- 0.119 and 0.355 +/- 0.131 ng/ml, *P < 0.05 vs. fasting, P < 0.01 vs. 30 min). The insulinogenic index correlated with the change in thioredoxin levels (r = 0.34, P < 0.05). However, there was no relationship with the change in 8-OHdG levels from 0 to 30 min. CONCLUSIONS: Hyperglycaemia in response to oral glucose impairs pancreatic B-cell function with decreasing thioredoxin levels. The augmented oxidative stress induced by hyperglycaemia may affect the cellular redox state. These findings strongly suggest that repeated postprandial hyperglycaemia may play an important role in the development and progression of diabetes mellitus.     

Advanced glycation endproducts: what is their relevance to diabetic complications?

Glycation is a major cause of spontaneous damage to proteins in physiological systems. This is exacerbated in diabetes as a consequence of the increase in glucose and other saccharides derivatives in plasma and at the sites of vascular complications. Protein damage by the formation of early glycation adducts is limited to lysine side chain and N-terminal amino groups whereas later stage adducts, advanced glycation endproducts (AGEs), modify these and also arginine and cysteine residues. Metabolic dysfunction in vascular cells leads to the increased formation of methylglyoxal which adds disproportionately to the glycation damage in hyperglycaemia. AGE-modified proteins undergo cellular proteolysis leading to the formation and urinary excretion of glycation free adducts. AGEs may potentiate the development of diabetic complications by activation of cell responses by AGE-modified proteins interacting with specific cell surface receptors, activation of cell responses by AGE free adducts, impairment of protein-protein and enzyme-substrate interactions by AGE residue formation, and increasing resistance to proteolysis of extracellular matrix proteins. The formation of AGEs is suppressed by intensive glycaemic control, and may in future be suppressed by thiamine and pyridoxamine supplementation, and several other pharmacological agents. Increasing expression of enzymes of the enzymatic defence against glycation provides a novel and potentially effective future therapeutic strategy to suppress protein glycation.     

Glycated haemoglobin as a predictor for metabolic syndrome in non-diabetic Korean adults.

AIMS: With increasing prevalence of diabetes mellitus and metabolic syndrome (MS), the importance of early detection of insulin resistance is emphasized. However, a simple and practical method of measurement is not readily available. Therefore, we examined the sensitivity and specificity of HbA(1c) for predicting impaired fasting glucose (IFG) and MS and its association with cardiovascular risk factors, particularly in the normal range of HbA(1c) levels in non-diabetic Korean subjects. METHODS: In 40,155 participants (median age 40 years) participating in a medical check-up programme, analysis of the distribution of HbA(1c) and its association with various cardiovascular risk factors was performed. In 22,465 selected participants, an analysis was conducted of the ability of HbA(1c) to predict MS and IFG. Anthropometric measurements were made in all subjects and fasting glucose, lipid profiles and HbA(1c) were measured. The presence of MS was defined according to the definitions of the Adult Treatment Panel III (ATP III) guideline and the new International Diabetes Federation (IDF) guideline. Patients with diabetes were excluded from the study. RESULTS: The incidence of MS was 12.2% according to ATP III criteria and 7.6% according to IDF criteria. When subjects were grouped by quartile of HbA(1c), cardiovascular risk factors significantly increased as the HbA(1c) increased. An HbA(1c) of 5.45% predicted the presence of MS (ATP III: sensitivity/specificity 57.4/64.3%, area under the curve 64.8%; IDF: sensitivity 60.2/63.4%, area under the curve 66.1%) and fasting blood glucose > or = 5.6 mmol/l (sensitivity/specificity 53.7/70%, area under the curve 66.1%). When the analyses were done separately by gender, female subjects showed higher cut-off of HbA(1c) for the prediction of MS (5.55% for both ATP III and IDF criteria). CONCLUSIONS: HbA(1c) increased as cardiovascular risk factors increased and HbA(1c) of 5.45% predicted the presence of MS. HbA(1c) might be a predictive measure of IFG and MS, and also cardiovascular risk factors in the Korean population.     

Endothelium-dependent and independent vasodilation studied at normoglycaemia in Type I diabetes mellitus with and without microalbuminuria

Aims/hypothesis. We examined whether endothelial function is impaired in patients with Type I (insulin-dependent) diabetes mellitus under conditions of near-normoglycaemia compared with age-matched healthy control subjects. Our aim was to determine whether microalbuminuria is associated with endothelial dysfunction in Type I diabetes. Methods. Endothelial function, measured as post-ischaemic flow-mediated dilatation of the brachial artery using ultrasound, was compared among 17 microalbuminuric and 17 normoalbuminuric diabetic patients, and 17 control subjects. Glyceryl trinitrate-mediated dilatation of the brachial artery was used to measure endothelium-independent function. All diabetic patients were studied at near-normoglycaemia, using insulin and 5 % dextrose infusions to maintain blood glucose between 3.5 and 8.0 mmol/l. Results. Flow-mediated dilatation was significantly lower in microalbuminuric diabetic patients (3.2 ± 0.3 %) compared with normoalbuminuric diabetic patients (5.4 ± 0.6 %) and control subjects (7.9 ± 0.6 %, p < 0.001). Normoalbuminuric diabetic patients also had significantly lower flow-mediated dilatation than control subjects (p = 0.01). Glyceryl trinitrate mediated dilatation was significantly lower in the microalbuminuric patients compared with the control subjects (11.9 ± 1.1 % vs 20.0 ± 1.2 %, p = 0.001). Albumin excretion rate and glycated haemoglobin showed a significant negative independent correlation with flow-mediated dilatation (both p < 0.05). Conclusion/interpretation. Type I diabetic patients show endothelial dysfunction at near-normoglycaemia compared with the control subjects, and this abnormality is more marked in diabetic patients with microalbuminuria. Endothelial dysfunction in Type I diabetes is related to the albumin excretion rate and glycaemic control. The presence of endothelial dysfunction in normoalbuminuric diabetic patients suggests it could precede microalbuminuria as an early risk marker for cardiovascular disease. [Diabetologia (2001) 44: 593–601] Received: 6 November 2000 and in revised form: 11 January 2001     

Pharmaceutical care of patients with gestational diabetes mellitus

Rationale, aims and objective To investigate whether the introduction of a programme of optimising drug treatment, intensive education and self‐monitoring of patients diagnosed with gestational diabetes mellitus (GDM) at an early stage (<20 gestational weeks), will improve management outcomes as determined by objective measures of patient knowledge about diabetes, glycaemia control, maternal/neonatal complications, and health‐related quality of life. Methods The study was a randomized, controlled, longitudinal, prospective clinical trial performed at Al‐Ain Hospital, Al‐Ain, United Arab Emirates. Over an 18‐month period, patients diagnosed with GDM were recruited and were randomly assigned to either an intervention or a control group, in a ratio of 3:2. Intervention patients received a structured pharmaceutical care service (including education and introduction of intensive self‐monitoring) while control patients received traditional services. Patients were followed up from time of recruitment until 6 months postnatally at scheduled outpatient clinics. A range of clinical and humanistic outcome measures, including maternal and neonatal complications, were used to assess the impact of the intervention. Results A total of 165 patients (99 intervention, 66 control) completed the study. The intervention patients exhibited a range of benefits from the provision of the programme when compared with control group patients. Statistically significant (P < 0.05) improvements were shown in the intervention group for knowledge of diabetes, health‐related quality of life (as determined by the SF36), control of plasma glucose and HbA_1c, maternal complications [e.g. decreased incidence of pre‐eclampsia (5.1% vs. 16.7%), eclampsia (1.0% vs. 7.6%), episodes of severe hyperglycaemia (3.0% vs. 19.7%) and need for Caesarean section (7.1% vs. 18.2%)], and neonatal complications [e.g. decreased incidence of neonatal hypoglycaemia (2.0% vs. 10.6%), respiratory distress at birth (4.0% vs. 15.2%), hyperbilirubinaemia (1.0% vs. 12.1%) and large for gestational age (9.0% vs. 22.7%)]. Conclusion The research provides clear evidence that provision of pharmaceutical care adds value to the management of GDM as exemplified by improved maternal and neonatal outcomes.     

Modulation of insulin action

Insulin is a key hormone regulating the control of metabolism and the maintenance of normoglycaemia and normolipidaemia. Insulin acts by binding to its cell surface receptor, thus activating the receptors intrinsic tyrosine kinase activity, resulting in receptor autophosphorylation and phosphorylation of several substrates. Tyrosine phosphorylated residues on the receptor itself and on subsequently bound receptor substrates provide docking sites for downstream signalling molecules, including adapters, protein serine/threonine kinases, phosphoinositide kinases and exchange factors. Collectively, those molecules orchestrate the numerous insulin-mediated physiological responses.A clear picture is emerging of the way in which insulin elicits several intracellular signalling pathways to mediate its physiologic functions. A further challenge, being pursued by several laboratories, is to understand the molecular mechanisms that underlie insulin action at the peripheral level, deregulation of which ultimately leads to hyperglycaemia and Type 2 diabetes.We review how circulating factors such as insulin itself, TNF-, interleukins, fatty acids and glycation products influence insulin action through insulin signalling molecules themselves or through other pathways ultimately impinging on the insulin-signalling pathway. Understanding how the mechanism by which molecular insulin action is modulated by these factors will potentially provide new targets for pharmacological agents, to enable the control of altered glucose and lipid metabolism and diabetes.Abbreviations AMPK Adenosine 5-monophosphate-activated protein kinase - Erk1/2 extracellular regulated kinase 1 and 2 - GSK-3 glycogen synthase kinase 3 - IKK inhibitor kappa B kinase - IR insulin receptor - JAKs janus kinases - JNK jun amino terminal kinase - MAPK mitogen activated protein kinase - PI3K phosphoinositide 3-kinase - PKB protein kinase B - PKC protein kinase C - S/T serine/threonine - SOCS suppressor of cytokine signalling - TOR target of rapamycin